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Understanding and controlling chronic inflammation using a novel laboratory model

Photo: Siddharth Kankaria / Research Matters

When bacteria or viruses enter our body, our immune system attacks these invaders through its first line of defense – inflammation – and helps us eject them. The inflammation generally dies down soon after. However, sometimes, our body can experience a long lasting immune response leading to chronic conditions such as osteoarthritis and fibrosis. This response, occurring in the absence of a bacterial or viral infection, is called a ‘sterile inflammation’. What causes such inflammations and how do we treat them? In a recent study, Dr. Srikala Raghavan and her team at the Institute for Stem Cell Biology and Regenerative Medicine (inStem), Bangalore, try to answer these intriguing questions.

The researchers have developed a laboratory model to study sterile inflammation and have designed and tested a new drug delivery system that can be used to treat disorders emerging from sterile or chronic inflammation.  Using a mouse model, they have investigated how the deletion of a protein called beta-integrin 1 from skin cells can initiate a chronic inflammatory response and recruit large numbers of immune cells even in the absence of any infection. “What is remarkable in our model is that although the loss of beta-integrin 1 degraded the basement membrane of the skin that anchors and nourishes the skin cells, the skin barrier remained completely intact, strongly suggesting that the inflammatory response is not caused due to a foreign invading agent”, explains Dr. Raghavan. “Therefore, our system is ideal to study sterile inflammation, and can capture the damage-associated molecular signature orchestrated by non-pathogenic attacks such as by inhaling asbestos or silica as well”, she adds.

In the same study, the authors also showed that this inflammatory response could be abrogated by treatment with anti-inflammatory drugs. But, chronic inflammation in mice builds up while they are still developing from an embryo in their mothers’ bodies. “We needed to devise an innovative way to prevent this, so we took the challenge to design a localized drug delivery system to deliver the drugs in pregnant mice. This is where the expertise of Dr. Praveen Vemula in biomaterials and drug delivery systems fit perfectly, and we collaborated with him”, mentions Dr. Raghavan.

The researchers were taken by surprise by the response of the infection to the new drug delivery methodology. “We expected only 10-20% of drug delivery, but the efficiency of drug delivery as well as the outcome of drug treatment were phenomenal. Both the disruption of basement membrane, and the recruitment of immune cells – the two hallmarks of sterile inflammation – were significantly curtailed upon drug treatment. Furthermore, we also provide a proof-of-concept for this novel mode of drug delivery, and we are excited about its future applications”, says Dr. Vemula.

The study also opens up the possibilities of novel therapeutic interventions against some of the common conditions. “These advances in identifying and modulating the underlying signals of sterile inflammation will be crucial for addressing an unmet need to intervene in early stages of sterile inflammation and eventually develop targeted therapies for chronic inflammatory disease such as arthritis and fibrosis”, opine Ms. Ambika S Kurbet and Mr. Samarth Hegde, the lead authors, stressing the importance of their study.

The study not only provides a fantastic model system to further dissect early molecular events during sterile inflammation, but also illustrates a promising novel mode for drug delivery. “Our fascinating collaboration with Dr. Praveen Vemula allowed us to deliver drugs appropriately in female pregnant mice in a set of challenging experiments, and study and control the immune response in the presence of an intact skin barrier. This work would not have been possible without the excellent collaborative atmosphere here at inStem”, signs off Dr. Raghavan.